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Quinoline analogs as phosphatidylinositol 3-kinase inhibitors

Active Publication Date: 2019-12-05
NANJING ZHENGXIANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

This patent describes a compound (A) that can inhibit the growth of cancer cells and make them sensitive to chemotherapy. The compound can be administered to cancer patients with chemotherapy to enhance its effectiveness.

Problems solved by technology

However, the U.S. label for idelalisib has a boxed warning describing toxicities that can be serious and fatal, including liver toxicity.

Method used

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  • Quinoline analogs as phosphatidylinositol 3-kinase inhibitors
  • Quinoline analogs as phosphatidylinositol 3-kinase inhibitors
  • Quinoline analogs as phosphatidylinositol 3-kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Fluoro-2-pyridin-2-yl-quinolin-3-yl)-ethylamine (9)

[0065]Step 1:

[0066]To a solution of 2-chloro-8-fluoroquinoline-3-carboxaldehyde (1.5 g, 7.2 mmol) in anhydrous THF (20 mL) was added titanium isopropoxide (4.3 mL, 1.4 mmol) at r.t. After 15 minutes, (R)-2-methyl-2-propanesulfinamide (0.867 g, 7.2 mmol) was added and stirring was continued overnight at r.t. Water (100 mL) was added to the reaction mixture and the precipitate obtained was filtered and washed with DCM. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give the crude material as a pale yellow solid which was purified by column chromatography on silica gel (EtOAc / hexane, 4 / 5)) to give a pale yellow solid (2.0 g, 89%). Mass Spectrum (ESI) m / e: 313 (M+1).

[0067]Step 2:

[0068]To a solution of 2-Methyl-propane-2-sulfinic acid 2-chloro-8-fluoro-quinolin-3-ylmethyleneamide (0.95 g, 2.8 mmol) in DCM (22 mL) was added dropwise MeMgCl (1.94 mL, 5.8 mmol; 3 M in THF) over 10 minutes at −78° C. under nitrog...

example 2

Fluoro-2-phenyl-quinolin-3-yl)-ethylamine (12)

[0074]

[0075]Compound (S)-2-(1-(2-Chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione was prepared according to the literature (J. Med. Chem. 2015, 58, 480-511). This compound (280 mg, 0.79 mmol), phenylboronic acid (146 mg, 1.2 mmol), and potassium carbonate (328 mg, 2.4 mmol) were combined in 6 mL of anhydrous DMF under an atmosphere of N2. The solution was purged with N2 for ˜5 min before adding PdCl2(dppf)DCM (64 mg, 0.079 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (12 mL). The organic layers were then washed with water (3×3 mL), followed by brine (10 mL). The combined aq. layers were extracted with DCM (3×2 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% to...

example 3

fluoro-2-(pyridin-2-yl) quinolin-3-yl)ethanamine (13)

[0078]

[0079]A mixture of (S)-2-(1-(2-chloro-7-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (0.86 g, 2.4 mmol), Pd(PPh3)4 (0.28 g, 0.24 mmol, 0.1 eq) and 2-(tributylstannyl)-pyridine (1.07 g, 2.9 mmol, 1.2 eq) in dioxane (30 mL) was heated to 90° C. under N2. After stirring overnight, LC-MS showed 30% completion. The reaction mixture was heated to 101° C. for additional 2 days. The reaction mixture was then cooled to rt and the resulted solid was filtered and washed with EtOAc to give a tan solid of 2-((S)-1-(7-fluoro-2(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione was obtained (0.84 g, 88%). Mass Spectrum (ESI) m / e: 398 (M+1).

[0080]To a slurried suspension of 2-((S)-1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (0.84 g, 2.1 mmol) in anhydrous ethanol (5 mL) was added NH2NH2 (0.34 g, 10.4 mmol) dropwise. The reaction mixture was heated to 90° C. for 30 min and cooled to rt. The reaction mixture w...

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Abstract

The present disclosure provides selective phosphoinositide 3-kinase inhibitors of formula (A), or pharmaceutically acceptable salts thereof. These compounds are useful for the treatment of conditions mediated by one or more P13K isoforms, such as PI3K delta (PI3Kδ). The present disclosure further provides methods of inhibiting phosphoinositide 3-kinase inhibitors using these compounds for treatment of disorders related to phosphatidylinositol 3-kinase activity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62 / 304,148, filed on Mar. 4, 2016, the disclosure of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present disclosure relates generally to quinoline analogs as inhibitors of phosphatidylinositol 3-kinase (PI3K) activity. More specifically, the invention further relates to the preparation of the disclosed PI3K inhibitor analogs and their use in pharmaceutical compositions for the treatment of various diseases, conditions and disorders related to PI3K activity.BACKGROUND OF THE INVENTION[0003]The class I phosphoinositide 3-kinases (PI3Ks) regulate phosphatidylinositol 4,5-bisphosphate (PIP2) phosphorylation. PI3K Converts PIP2 to the scaffolding binding element phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 plays a key regulatory role in cell survival, signal transduction, control of membrane trafficking a...

Claims

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Application Information

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IPC IPC(8): A61K31/506
CPCA61K31/506C07D401/12C07D401/14A61K45/06A61P11/00A61P37/08A61P37/00A61P29/00A61P35/02A61P35/00A61P25/00A61P1/18A61P13/12A61P37/06A61P43/00C07D487/04
Inventor HAO, XIAOLIN
Owner NANJING ZHENGXIANG PHARMA CO LTD
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